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The vacuolar proton-translocating ATPase (V-ATPase) is a transmembrane multi-protein complex fundamental in maintaining a normal intracellular pH. In the tumoral contest, its role is crucial since the metabolism underlying carcinogenesis is mainly based on anaerobic glycolytic reactions. Moreover, neoplastic cells use the V-ATPase to extrude chemotherapy drugs into the extra-cellular compartment as a drug resistance mechanism. In glioblastoma (GBM), the most malignant and incurable primary brain tumor, the expression of this pump is upregulated, making it a new possible therapeutic target. In this work, the bafilomycin A1-induced inhibition of V-ATPase in patient-derived glioma stem cell (GSC) lines was evaluated together with temozolomide, the first-line therapy against GBM. In contrast with previous published data, the proposed treatment did not overcome resistance to the standard therapy. In addition, our data showed that nanomolar dosages of bafilomycin A1 led to the blockage of the autophagy process and cellular necrosis, making the drug unusable in models which are more complex. Nevertheless, the increased expression of V-ATPase following bafilomycin A1 suggests a critical role of the proton pump in GBM stem components, encouraging the search for novel strategies to limit its activity in order to circumvent resistance to conventional therapy. [ABSTRACT FROM AUTHOR]

Background: The exoscope is a high-definition telescope recently introduced in neurosurgery. In the past few years, several reports have described the advantages and disadvantages of such technology. No studies have compared results of surgery with standard microscope and exoscope in patients with glioblastoma multiforme (GBM). Methods: Our retrospective study encompassed 177 patients operated on for GBM (WHO 2021) between February 2017 and August 2022. A total of 144 patients were operated on with a microscope only and the others with a 3D4K exoscope only. All clinical and radiological data were collected. Progression-free survival (PFS) and overall survival (OS) have been estimated in the two groups and compared by the Cox model adjusting for potential confounders (e.g., sex, age, Karnofsky performance status, gross total resection, MGMT methylated promoter, and operator's experience). Results: IDH was mutated in 9 (5.2%) patients and MGMT was methylated in 76 (44.4%). Overall, 122 patients received a gross total resection, 14 patients received a subtotal resection, and 41 patients received a partial resection. During follow-up, 139 (73.5%) patients experienced tumor recurrence and 18.7% of them received a second surgery. After truncation to 12 months, the median PFS for patients operated on with the microscope was 8.82 months, while for patients operated on with the exoscope it was >12 months. Instead, the OS was comparable in the two groups. The multivariable Cox model showed that the use of microscope compared to the exoscope was associated with lower progression-free survival (hazard ratio = 3.55, 95%CI = 1.66–7.56, p = 0.001). Conclusions: The exoscope has proven efficacy in terms of surgical resection, which was not different to that of the microscope. Furthermore, patients operated on with the exoscope had a longer PFS. A comparable OS was observed between microscope and exoscope, but further prospective studies with longer follow-up are needed. [ABSTRACT FROM AUTHOR]

Simple Summary: The purpose of this review stems from the need, based on the incidence of brain metastases, to investigate the roles of some intraoperative adjuncts. Surgery still plays a central role in the treatment of this disease for an optimal local control of the disease. It is therefore essential to know all the tools that can help to achieve this goal safely and with maximum results. To this end, intraoperative tumour enhancing methods and intraoperative visualisation systems were examined. (1) Background: brain metastases (BMs) are the most common neoplasm of the central nervous system; despite the high incidence of this type of tumour, to date there is no universal consensus on the most effective treatment in patients with BMs, even if surgery still plays a primary role. Despite this, the adjunct systems that help to reach the GTR, which are well structured for other tumour forms such as ultrasound and fluorescence systems, are not yet well employed and standardised in surgical practice. The aim of this review is to provide a picture of the current state-of-art of the roles of iOUS and intraoperative fluorescence to better understand their potential roles as surgical tools. (2) Methods: to reach this goal, the PubMed database was searched using the following string as the keyword: (((Brain cerebral metastasis [MeSH Major Topic])OR (brain metastasis, [MeSH Major Topic])) AND ((5-ala, [MeSH Terms]) OR (Aminolevulinicacid [All fields]) OR (fluorescein, [MeSH Terms]) OR (contrast enhanced ultrasound [MeSH Terms])OR ((intraoperative ultrasound. [MeSH Terms]))) AND (english [Filter]) AND ((english [Filter]) AND (2010:2022 [pdat])) AND (english [Filter]). (3) Results: from our research, a total of 661 articles emerged; of these, 57 were selected. 21 of these included BMs generically as a secondary class for comparisons with gliomas, without going deeply into specific details. Therefore, for our purposes, 36 articles were considered. (4) Conclusions: with regard to BMs treatment and their surgical adjuncts, there is still much to be explored. This is mainly related to the heterogeneity of patients, the primary tumour histology and the extent of systemic disease; regardless, surgery plays a paramount role in obtaining a local disease control, and more standardised surgical protocols need to be made, with the aim of optimizing the use of the available surgical adjuncts and in order to increase the rate of GTR. [ABSTRACT FROM AUTHOR]

Despite the efforts made in recent decades, glioblastoma is still the deadliest primary brain cancer without cure. The potential role in tumour maintenance and progression of the peritumoural brain zone (PBZ), the apparently normal area surrounding the tumour, has emerged. Little is known about this area due to a lack of common definition and due to difficult sampling related to the functional role of peritumoural healthy brain. The aim of this work was to better characterize the PBZ and to identify genes that may have role in its malignant transformation. Starting from our previous study on the comparison of the genomic profiles of matched tumour core and PBZ biopsies, we selected CDK4 and EXT2 as putative malignant drivers of PBZ. The gene expression analysis confirmed their over-expression in PBZ, similarly to what happens in low-grade glioma and glioblastoma, and CDK4 high levels seem to negatively influence patient overall survival. The prognostic role of CDK4 and EXT2 was further confirmed by analysing the TCGA cohort and bioinformatics prediction on their gene networks and protein–protein interactions. These preliminary data constitute a good premise for future investigations on the possible role of CDK4 and EXT2 in the malignant transformation of PBZ. [ABSTRACT FROM AUTHOR]

Simple Summary: Medulloblastoma is the most common malignant brain tumor in children. In a subset of cases, a causal factor is a constitutive mutation of the TP53 gene, which may be inherited or arise for the first time in a patient (de novo). Using an immunohistochemistry assay as a screening tool, we selected patients suspected of harboring a TP53 mutation and offered genetic counseling and germline testing. Our study, which was the first to investigate the parental origin of TP53 mutations in medulloblastoma, allowed the identification of two additional cases with de novo mutations. Moreover, we demonstrated that in one patient the mutation originated at a post-zygotic stage, resulting in somatic mosaicism. These findings have important implications for genetic counseling since they highlight the occurrence of both pre- and post-zygotic TP53 de novo mutations in medulloblastoma, pointing out that in a specific subgroup of patients genetic testing should be offered regardless of family history. Li-Fraumeni syndrome (LFS) is an autosomal dominant disorder caused by mutations in the TP53 gene, predisposing to a wide spectrum of early-onset cancers, including brain tumors. In medulloblastoma patients, the role of TP53 has been extensively investigated, though the prevalence of de novo mutations has not been addressed. We characterized TP53 mutations in a monocentric cohort of consecutive Sonic Hedgehog (SHH)-activated medulloblastoma patients. Germline testing was offered based on tumor p53 immunostaining positivity. Among 24 patients, three (12.5%) showed tumor p53 overexpression, of whom two consented to undergo germline testing and resulted as carriers of TP53 mutations. In the first case, family history was uneventful and the mutation was not found in either of the parents. The second patient, with a family history suggestive of LFS, unexpectedly resulted as a carrier of the mosaic mutation c.742=/C>T p.(Arg248=/Trp). The allele frequency was 26% in normal tissues and 42–77% in tumor specimens. Loss of heterozygosity (LOH) in the tumor was also confirmed. Notably, the mosaic case has been in complete remission for more than one year, while the first patient, as most TP53-mutated medulloblastoma cases from other cohorts, showed a severe and rapidly progressive disease. Our study reported the first TP53 mosaic mutation in medulloblastoma patients and confirmed the importance of germline testing in p53 overexpressed SHH-medulloblastoma, regardless of family history. [ABSTRACT FROM AUTHOR]

Venous thromboembolism (VTE) is a common complication of cancer that severely increases morbidity and mortality. Patients with intracranial tumors are more likely to develop VTE than patients with cancers at other sites. Conversely, limited tools exist to identify patients with high thrombotic risk. Upon activation, neutrophils release their content through different mechanisms triggering thrombosis. We explored the ability of microRNAs (miRNAs) and plasma markers of neutrophil activation measured before surgery to predict the risk of early post-surgical pulmonary embolism (PE) in glioma and meningioma patients. We recruited and prospectively followed 50 patients with glioma and 50 with meningioma, 34% of whom in each group developed an early objectively-diagnosed post-surgical PE. We measured miRNA expression and neutrophil markers (cell-free DNA, nucleosomes, calprotectin and myeloperoxidase) before surgery. In glioma patients, we adjusted and validated a predictive model for post-surgical PE with 6 miRNAs: miR-363-3p, miR-93-3p, miR-22-5p, miR-451a, miR-222-3p and miR-140-3p (AUC = 0.78; 95% Confidence Interval (CI) [0.63, 0.94]) and another with cfDNA and myeloperoxidase as predictors (AUC = 0.71; 95% CI [0.52, 0.90]). Furthermore, we combined both types of markers and obtained a model with myeloperoxidase and miR-140-3p as predictors (AUC = 0.79; 95% CI [0.64, 0.94]). In meningioma patients we fitted and validated a predictive model with 6 miRNAs: miR-29a-3p, miR-660-5p, miR-331-3p, miR-126-5p, miR-23a-3p and miR-23b-3p (AUC = 0.69; 95% CI [0.52, 0.87]). All our models outperformed the Khorana score. This is the first study that analyzes the capability of plasma miRNAs and neutrophil activation markers to predict early post-surgical PE in glioma and meningioma patients. The estimation of the thrombotic risk before surgery may promote a tailored thromboprophylaxis in a selected group of high-risk patients, in order to minimize the incidence of PE and avoid bleedings. [ABSTRACT FROM AUTHOR]

Circulating platelets (PLTs) are able to affect glioblastoma (GBM) microenvironment by supplying oncopromoter and pro-angiogenic factors. Among these mediators, sphingosine-1-phophate (S1P) has emerged as a potent bioactive lipid enhancing cell proliferation and survival. Here, we investigated the effect of "tumor education", characterizing PLTs from GBM patients in terms of activation state, protein content, and pro-angiogenic potential. PLTs from healthy donors (HD-PLTs) and GBM patients (GBM-PLTs) were collected, activated, and analyzed by flow cytometry, immunofluorescence, and Western blotting. To assess the pro-angiogenic contribution of GBM-PLTs, a functional cord formation assay was performed on GBM endothelial cells (GECs) with PLT-releasate. GBM-PLTs expressed higher positivity for P-selectin compared to HD-PLTs, both in basal conditions and after stimulation with adenosine triphosphate (ADP) and thrombin receptor activating peptide (TRAP). PLTs showed higher expression of VEGFR-1, VEGFR-2, VWF, S1P, S1PR1, SphK1, and SPNS. Interestingly, increased concentrations of VEGF and its receptors VEGFR1 and VEGFR2, VWF, and S1P were found in GBM-PLT-releasate with respect to HD-PLTs. Finally, GBM-PLT-releasate showed a pro-angiogenic effect on GECs, increasing the vascular network's complexity. Overall, our results demonstrated the contribution of PLTs to GBM angiogenesis and aggressiveness, advancing the potential of an anti-PLT therapy and the usefulness of PLT cargo as predictive and monitoring biomarkers. [ABSTRACT FROM AUTHOR]